KMT2C mutations in diffuse-type gastric adenocarcinoma promote epithelial-to-mesenchymal transition Journal Article

Authors: Cho, S. J.; Yoon, C.; Lee, J. H.; Chang, K. K.; Lin, J. X.; Kim, Y. H.; Kook, M. C.; Aksoy, B. A.; Park, D. J.; Ashktorab, H.; Smoot, D. T.; Schultz, N.; Yoon, S. S.
Article Title: KMT2C mutations in diffuse-type gastric adenocarcinoma promote epithelial-to-mesenchymal transition
Abstract: Purpose: Lauren diffuse-type gastric adenocarcinomas (DGAs) are generally genomically stable. We identified lysine (K)-specific methyltransferase 2C (KMT2C) as a frequently mutated gene and examined its role in DGA progression. Experimental Design: We performed whole exome sequencing on tumor samples of 27 patients with DGA who underwent gastrectomy. Lysine (K)-specific methyltransferase 2C (KMT2C) was analyzed in DGA cell lines and in patient tumors. Results: KMT2C was the most frequently mutated gene (11 of 27 tumors [41%]). KMT2C expression by immunohistochemistry in tumors from 135 patients with DGA undergoing gastrectomy inversely correlated with more advanced tumor stage (P 1⁄4 0.023) and worse overall survival (P 1⁄4 0.017). KMT2C shRNA knockdown in nontransformed HFE-145 gastric epithelial cells promoted epithelial-to-mesenchymal transition (EMT) as demonstrated by increased expression of EMT-related proteins N-cadherin and Slug. Migration and invasion in gastric epithelial cells following KMT2C knockdown increased by 47- to 88-fold. In the DGA cell lines MKN-45 and SNU-668, which have lost KMT2C expression, KMT2C re-expression decreased expression of EMT-related proteins, reduced cell migration by 52% to 60%, and reduced cell invasion by 50% to 74%. Flank xenografts derived from KMT2C-expressing DGA organoids, compared with wild-type organoids, grew more slowly and lost their infiltrative leading edge. EMT can lead to the acquisition of cancer stem cell (CSC) phenotypes. KMT2C re-expression in DGA cell lines reduced spheroid formation by 77% to 78% and reversed CSC resistance to chemotherapy via promotion of DNA damage and apoptosis. Conclusions: KMT2C is frequently mutated in certain populations with DGA. KMT2C loss in DGA promotes EMT and is associated with worse overall survival. © 2018 American Association for Cancer Research.
Keywords: immunohistochemistry; adult; controlled study; gene mutation; human cell; major clinical study; overall survival; clinical trial; advanced cancer; cancer growth; cancer staging; prospective study; phenotype; dna damage; apoptosis; gene expression; cohort analysis; retrospective study; wild type; correlation analysis; xenograft; cancer stem cell; cell migration; epithelium cell; gastrectomy; genome; stomach adenocarcinoma; cadherin; cell invasion; histone lysine methyltransferase; epithelial mesenchymal transition; tumor spheroid; gene knockdown; human; male; female; priority journal; article; whole exome sequencing; organoid; kmt2c gene; gastric diffuse adenocarcinoma cell line
Journal Title: Clinical Cancer Research
Volume: 24
Issue: 24
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2018-12-15
Start Page: 6556
End Page: 6569
Language: English
DOI: 10.1158/1078-0432.Ccr-17-1679
PROVIDER: scopus
PMCID: PMC6295255
PUBMED: 30108106
Notes: Clin. Cancer Res. -- Export Date: 2 January 2019 -- Article -- CODEN: CCREF C2 - 30108106 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Sam Yoon
    53 Yoon
  2. Nikolaus D Schultz
    193 Schultz
  3. Bulent Arman Aksoy
    33 Aksoy
  4. Do Joong Park
    15 Park
  5. Changhwan Yoon
    25 Yoon
  6. Soo Jeong   Cho
    4 Cho
  7. Jun Ho   Lee
    4 Lee
  8. Kevin   Chang
    11 Chang
  9. Jianxian Lin
    1 Lin